VHL and HIF-1α: gene variations and prognosis in early-stage clear cell renal cell carcinoma

Von Hipple-Lindau gene (VHL) inactivation represents the most frequent abnormality in clear cell renal cell carcinoma (ccRCC). Hypoxia-inducible factor-1 alpha (HIF-1 alpha) expression is regulated by O-2 level. In normal O-2 conditions, VHL binds HIF-1 alpha and allows HIF-1 alpha proteasomal degradation. A single-nucleotide polymorphism (SNP) has been found located in the oxygen-dependent degradation domain at codon 582 (C1772T, rs11549465, Pro582Ser). In hypoxia, VHL/HIF-1 alpha interaction is abolished and HIF-1 alpha activates target genes in the nucleus. This study analyzes the impact of genetic alterations and protein expression of VHL and the C1772T SNP of HIF-1 alpha gene (HIF-1 alpha) on prognosis in early-stage ccRCC (pT1 alpha, pT1b, and pT2). Mutational analysis of the entire VHL sequence and the genotyping of HIF-1 alpha C1772T SNP were performed together with VHL promoter methylation analysis and loss of heterozygosis (LOH) analysis at (3p25) locus. Data obtained were correlated with VHL and HIF-1 alpha protein expression and with tumor-specific survival (TSS). VHL mutations, methylation status, and LOH were detected in 51, 11, and 12 % of cases, respectively. Our results support the association between biallelic alterations and/or VHL silencing with a worse TSS. Moreover, we found a significant association between the HIF-1 alpha C1772C genotype and a worse TSS. The same association was found when testing the presence of HIF-1 alpha protein in the nucleus. Our results highlight the role of VHL/HIF-1 alpha pathway in RCC and support the molecular heterogeneity of earlystage ccRCC. More important, we show the involvement of HIF-1 alpha C1772T SNP in ccRCC progression.